Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced results from the pivotal neoadjuvant/adjuvant Phase 3 KEYNOTE-522 trial in patients with early-stage triple-negative breast cancer (TNBC). The trial investigated a regimen of neoadjuvant KEYTRUDA, Merck’s anti-PD-1 therapy, plus chemotherapy, followed by adjuvant KEYTRUDA as monotherapy (the KEYTRUDA regimen) compared with a regimen of neoadjuvant chemotherapy followed by adjuvant placebo (the chemotherapy-placebo regimen). Interim findings – which are from the first randomized trial of an anti-PD-1 therapy in the neoadjuvant/adjuvant setting for TNBC – are being presented today during the Presidential Symposium at the European Society for Medical Oncology (ESMO) 2019 Congress (Abstract #LBA8).

In the neoadjuvant phase, KEYTRUDA plus chemotherapy (n=401) resulted in a statistically significant increase in pathological complete response (pCR) versus chemotherapy (n=201), from 51.2% with neoadjuvant chemotherapy to 64.8% for neoadjuvant KEYTRUDA plus chemotherapy, in patients with early-stage TNBC (p=0.00055). Pathological complete response, one of the dual primary endpoints was defined as ypT0/Tis ypN0 (i.e., no invasive residual cancer in breast and lymph nodes). The improvement seen when adding KEYTRUDA to neoadjuvant chemotherapy was observed regardless of PD-L1 expression. In the other dual primary endpoint of event-free-survival (EFS), with a median follow-up of 15.5 months, the KEYTRUDA regimen reduced the risk of progression in the neoadjuvant phase and recurrence in the adjuvant phase by 37% – a favorable trend for EFS – compared with the chemotherapy-placebo regimen (HR=0.63 [95% CI, 0.43-0.93]). The safety profiles of KEYTRUDA and chemotherapy in KEYNOTE-522 were consistent with previous studies.

“This innovative trial is the first to employ combined neoadjuvant and adjuvant treatment with KEYTRUDA in patients with early-stage TNBC,” said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. “The results of the KEYNOTE-522 study, reported today, are very encouraging and have the potential to change the treatment of patients diagnosed with TNBC.”

“As an oncologist specializing in the treatment of TNBC, I am highly encouraged by the significant improvement in pCR rates with KEYTRUDA plus chemotherapy in the neoadjuvant setting and the positive trend for event free-survival demonstrated in this trial,” said Dr. Peter Schmid, lead, Centre for Experimental Cancer Medicine, Barts Cancer Institute. “There is significant need for new treatment regimens that can increase pCR rates in this patient population.”

As previously announced, KEYTRUDA plus chemotherapy was granted Breakthrough Therapy designation (BTD) by the U.S. Food and Drug Administration (FDA) for the neoadjuvant treatment of patients with high-risk, early-stage TNBC. The BTD was granted based on data from Phase 1b KEYNOTE-173 and Phase 2 I-SPY2 trial, which demonstrated encouraging anti-tumor activity with neoadjuvant KEYTRUDA plus chemotherapy in these patients.

“These findings from the KEYNOTE-522 trial are exciting for the TNBC community – a community in particular need of scientific advances,” said Hayley Dinerman, executive director, Triple Negative Breast Cancer Foundation. “We are committed to supporting patients with TNBC, and we are pleased to see new data focused on earlier lines of treatment.”

As previously announced, Merck plans to share early interim analysis data from KEYNOTE-522 with regulatory authorities. The company continues to progress a robust clinical development program for KEYTRUDA in breast cancer, which encompasses several internal studies and external collaborative trials, including KEYNOTE-355 and KEYNOTE-242.

Study Design and Additional Data from KEYNOTE-522 Trial (Abstract #LBA8)

KEYNOTE-522 is a Phase 3, randomized, double-blind trial (ClinicalTrials.gov, NCT03036488). The dual primary endpoints of pCR and EFS were evaluated based on a pre-specified group sequential approach. Secondary endpoints include: pCR rate using alternative definitions (ypT0 ypN0, i.e., no invasive or noninvasive residual cancer in breast and lymph nodes, and ypT0/Tis, i.e., no invasive residual tumor in breast at the time of definitive surgery); overall survival (OS); pCR, EFS and OS in patients whose tumors express PD-L1 combined positive score (CPS) ≥1; and safety. The study enrolled 1,174 patients who were randomized 2:1 to receive either:

• The KEYTRUDA regimen: KEYTRUDA (Q3W) plus paclitaxel (weekly) and carboplatin (weekly or Q3W) for four cycles, followed by KEYTRUDA plus cyclophosphamide and either doxorubicin or epirubicin (Q3W) for four cycles as neoadjuvant therapy prior to surgery, followed by nine cycles of KEYTRUDA (Q3W) as adjuvant monotherapy post-surgery (n=784) or;
• The chemotherapy-placebo regimen: Placebo (Q3W) plus paclitaxel (weekly) and carboplatin (weekly or Q3W) for four cycles, followed by placebo plus cyclophosphamide and either doxorubicin or epirubicin (Q3W) for four cycles, followed by nine cycles of placebo (Q3W) as adjuvant therapy post-surgery (n=390).

For secondary endpoints of pCR using alternative definitions, the rates of pCR defined as ypT0 ypN0 were 59.9% versus 45.3%, and the rates of pCR defined as ypT0/Tis were 68.6% versus 53.7% for neoadjuvant KEYTRUDA plus chemotherapy (n=401) versus neoadjuvant chemotherapy (n=201).

In an exploratory sub-group analysis of pCR based on PD-L1 expression, the improvement seen when adding KEYTRUDA to neoadjuvant chemotherapy was observed regardless of PD-L1 expression. In the PD-L1 CPS ≥1 subgroup, the rates of pCR were 68.9% for neoadjuvant KEYTRUDA plus chemotherapy (n=334) versus 54.9% for neoadjuvant chemotherapy (n=164). In the PD-L1 CPS<1 subgroup, the rates of pCR were 45.3% for neoadjuvant KEYTRUDA plus chemotherapy (n=64) versus 30.3% versus neoadjuvant chemotherapy (n=33).

During the neoadjuvant phase, treatment-related adverse events (TRAEs) of any grade occurred in 99.0% of patients receiving KEYTRUDA plus chemotherapy (n=781) and 99.7% of patients receiving chemotherapy (n=389). Grade 3-5 TRAEs occurred in 76.8% of patients receiving KEYTRUDA plus chemotherapy and 72.2% of patients receiving chemotherapy. The most common Grade 3-5 TRAEs (occurring in ≥10% of patients) were neutropenia (34.6%), decreased neutrophil count (18.7%), anemia (18.2%), and febrile neutropenia (17.7%) for KEYTRUDA plus chemotherapy and neutropenia (33.2%), decreased neutrophil count (23.1%), and anemia (14.9%) for chemotherapy. TRAEs resulting in discontinuation of any treatment occurred in 23.3% of patients receiving KEYTRUDA plus chemotherapy and 12.3% of patients receiving chemotherapy. TRAEs led to death in two patients receiving KEYTRUDA plus chemotherapy and one patient receiving chemotherapy.

During the adjuvant phase, TRAEs of any grade occurred in 48.1% of patients receiving KEYTRUDA (n=547) and 43.0% of patients receiving placebo (n=314). Grade 3-5 TRAEs occurred in 5.7% of patients receiving KEYTRUDA monotherapy and 1.9% of patients receiving placebo. There were no TRAEs occurring in ≥10% of patients. TRAEs resulting in discontinuation of treatment occurred in 3.3% of patients receiving KEYTRUDA monotherapy and 1.3% of patients receiving placebo. TRAEs led to death in one patient receiving KEYTRUDA monotherapy.

Immune-mediated adverse events and infusion reactions of any grade in the combined neoadjuvant and adjuvant phases occurred in 42.3% of patients receiving the KEYTRUDA regimen and 21.3% of patients receiving the chemotherapy-placebo regimen. The most common of these events (occurring in ≥10% of patients) were infusion reactions (17.7%) and hypothyroidism (14.9%) in the KEYTRUDA regimen and infusion reactions (11.6%) in the chemotherapy-placebo regimen. Immune-mediated adverse events led to death in one patient in the KEYTRUDA regimen.